Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila , zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.

RNA exosomes are multi-subunit complexes conserved throughout evolution1 and emerging as the major cellular machinery for processing, surveillance, and turnover of a diverse spectrum of coding and non-coding RNA substrates essential for viability2. By exome sequencing, we discovered recessive mutations in exosome component 3 (EXOSC3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly, and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 [PCH1; OMIM 607596]3–6. We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment with small brain and poor motility, reminiscent of human clinical features and largely rescued by coinjected wildtype but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome gene responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.

Pathfinding of growing neurites depends on turning of the growth cone in response to extracellular cues. Motile filopodia of the growth cone are known to be critical for mediating contact-dependent guidance of the growth cone. However, whether filopodia also play an essential role in growth cone turning response induced by a diffusible chemotropic substance is unclear. Growth cones of cultured Xenopus spinal neurons exhibited chemotropic turning responses in a gradient of glutamate within a limited range of concentrations. This turning response depends on the activation of the NMDA subtype of glutamate receptors and requires the presence of extracellular Ca2+. Time-lapse differential interference contrast microscopy with quantitative analysis of filopodia dynamics showed a close correlation between an increased number of filopodia on the side of the growth cone facing the glutamate source and the turning. Such filopodia asymmetry was observed within minutes after the onset of the glutamate gradient, before any detectable turning of the growth cone. In Ca(2+)-free medium, no filopodia asymmetry was induced by the glutamate gradient, and no growth cone turning was observed. Furthermore, elimination of filopodia with a low concentration of cytochalasin B completely abolished the turning response without substantially affecting neurite extension. Thus, filopodia may be required for chemotropic guidance of the growth cone, and an asymmetry in filopodia distribution may be an early cellular event responsible for determining the direction the growth cone advances.